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Pancreatic cancer is one of the most lethal digestive system cancers with a 5‐year survival rate of 4–7%. Despite extensive efforts, recent chemotherapeutic regimens have provided only limited benefits to pancreatic cancer patients. Gemcitabine and  TS ‐1, the current standard‐of‐care chemotherapeutic drugs for treatment of this severe cancer, have a low response rate. Hypoxia is one of the factors contributing to treatment resistance. Specifically, overexpression of hypoxia‐inducible factor, a master transcriptional regulator of cell adaption to hypoxia, is strongly correlated with poor prognosis in many human cancers.  TAT ‐ ODD ‐procaspase‐3 ( TOP 3) is a protein prodrug that is specifically processed and activated in hypoxia‐inducible factor‐active cells in cancers, leading to cell death. Here, we report combination therapies in which  TOP 3 was combined with gemcitabine or  TS ‐1. As monotherapy, gemcitabine and  TS ‐1 showed a limited effect on hypoxic and starved pancreatic cancer cells, whereas co‐treatment with  TOP 3 successfully overcame this limitation  in vitro . Furthermore, combination therapies of  TOP 3 with these drugs resulted in a significant improvement in survival of orthotopic pancreatic cancer models involving the human pancreatic cancer cell line  SUIT ‐2. Overall, our study indicates that the combination of  TOP 3 with current chemotherapeutic drugs can significantly improve treatment outcome, offering a promising new therapeutic option for patients with pancreatic cancer.

Hypoxia‐inducible factor‐targeting prodrug TOP 3 combined with gemcitabine or TS ‐1 improves pancreatic cancer survival in an orthotopic model